Treatment of Biliary Tract Cancers
Case Continued
CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.
- How is cholangiocarcinoma staged and classified?
The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).23
The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.42 Type II reach the confluence of the hepatic ducts.42 Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).42 Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.42 Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.42
- What is the first-line treatment for localized cholangiocarcinomas?
Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.44 Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.45 A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.45
Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.17 Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.43 Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.42,46
- Is there a role for adjuvant treatment?
Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.47 Initial recurrence at a distant site occurs in 40% to 50% of patients.48
Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.49 A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.49 Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.49 These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.50 Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.
In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m2 twice daily for days 1–14 every 21 days for 8 cycles).51 Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.
